TW201815383A - Multilayer beads for pharmaceutical use - Google Patents

Abstract

Multilayer beads for pharmaceutical use having a drug-in-polymer layer are disclosed. The disclosed multilayer beads for pharmaceutical use have (a) a core particle; (b) an optional barrier layer coated on the surface of the core particle; (c) a drug-in-polymer layer coated on the surface of the core or the barrier layer, (d) an optional sealant layer coated on the surface of the drug-in-polymer layer; and (e) optionally one or more outer layers external to the drug-in-polymer layer or the sealant layer. The drug-in-polymer layer consists essentially of (i) a drug selected from the group consisting of a 15-keto prostaglandin drug, a 13,14-dihydro prostaglandin drug, and a 13,14-dihydro-15-keto prostaglandin drug; and (ii) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer or a mixture thereof. The drug-in-polymer layer may be solid dispersion of the drug in the polymer. Pharmaceutical compositions comprising a plurality of multilayer beads and a pharmaceutically acceptable excipient and methods of treating a gastrointestinal disorder are also disclosed.

Description

Multilayer beads for pharmaceutical use

FIELD OF THE INVENTION The present invention relates to multi-layer beads, their preparation methods, and their pharmaceutical uses. More particularly, the present invention relates to a multilayer bead having a drug-in-polymer layer, wherein the drug is a 15-keto prostaglandin drug, 13,14-dihydroprostaglandin drug, or 13 , 14-dihydro-15-keto prostaglandin drug and the polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or a mixture thereof and used to treat gastrointestinal disorders.

BACKGROUND OF THE INVENTION Fatty acid derivatives exist in tissues or organs of humans and other mammals and exhibit a wide range of physiological activities. Prostaglandin is a fatty acid derivative with a prostaglandic acid structure represented by formula (A):

Some synthetic prostaglandin (PG) analogs have a modified prostaglandic acid structure and various chemical modifications. The main structures of such analogs are classified into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs, and PGJs according to the five-membered ring part, and they can be determined by the number of unsaturated bonds in the ω chain and Location is further classified into subtypes.

PGE ₁ derivatives are used to treat gastrointestinal disorders. For example, 15-keto-16-halogen prostaglandin compounds can be used as laxatives (US Patent No. 5,317,032). Lubiprostone (also known as 13,14-dihydro-15-keto-16,16-difluoro-PGE ₁₎ is an Amitiza® drug used to treat the following conditions Active pharmaceutical ingredients ("API" or "drug"), such as chronic idiopathic constipation in adults, opioid-induced constipation and intestinal dryness. Lubiprostone activates the type 2 chloride channel (ClC-2) and increases the secretion of chloride-rich liquid from the serosa to the mucosal side of the gastrointestinal tract.

In general, prostaglandins are insoluble in water and become significantly unstable in the presence of water. Furthermore, prostaglandins are unstable by themselves or in the presence of most solids or solvents. To address such challenges, encapsulated formulations containing 15-keto-16-difluoroprostaglandin compounds and solvents such as glycerides are described that can maintain the stability of the compound (US Patent No. 6,583,174). Amexia is formulated with chain fatty acid triglycerides (MCTs) in soft gelatin capsules with high storage stability, as described in US Patent No. 8,026,393.

Some patient groups, for example, children or the elderly, cannot swallow capsules or lozenges. This may complicate, reduce or even eliminate the possibility of treatment. There is a need to develop novel formulations that allow prostaglandins to be easily administered and suitable for such patient groups. The present invention addresses this need.

SUMMARY OF THE INVENTION The present invention relates to a multi-layer bead for pharmaceutical use, which has a polymer coating layer, wherein the drug is 15-keto prostaglandin drug, 13,14-dihydroprostaglandin drug, or 13,14- Dihydro-15-keto prostaglandin drug and the polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or a mixture thereof. More broadly, the present invention is applicable to fatty acid derivatives used as medicines and is described in US Patent No. 8,026,393, Formula I, the contents of which are expressly incorporated by reference. The present invention also relates to a pharmaceutical composition, which contains a plurality of the multi-layered beads and is used for the treatment of gastrointestinal disorders, especially gastrointestinal disorders of children, the elderly and individuals with dysphagia.

The present invention provides multi-layer beads for pharmaceutical use, comprising: (a) a core particle; (b) an optional barrier layer coated on the surface of the core particle; (c) a polymer drug coating layer , Which is coated on the surface of the core particle, or when the barrier layer is present, it is coated on the surface of the barrier layer, wherein the polymer drug-coated layer basically consists of the following: (i) a drug, Selected from the group consisting of: 15-keto prostaglandin drugs, 13,14-dihydroprostaglandin drugs, and 13,14-dihydro-15-keto prostaglandin drugs; and (ii) a polymer, Selected from the group consisting of: polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, or mixtures thereof; (d) an optional sealing layer, which is coated on the surface of the polymer drug-coated layer; And (e) optionally, one or more outer layers, which are outside the polymer-coated layer, or when the sealing layer is present, it is outside the sealing layer.

The present invention provides a pharmaceutical composition comprising a plurality of multilayer beads and a pharmaceutically acceptable excipient. The plurality of multi-layer beads combine to represent the therapeutically effective amount of the drug and can be the unit dose of the drug. Such pharmaceutical compositions usually exist in solid oral dosage forms.

The present invention also relates to a method of treating gastrointestinal disorders, the method comprising the step of orally administering a therapeutically effective amount of multilayer beads in the pharmaceutical composition according to the present invention to a patient in need thereof.

Another specific example of the present invention relates to a solid formulation or solid dispersion of a drug in a polymer, which basically consists of (a) a drug selected from the group consisting of: 15-keto prostaglandin drugs , 13,14-dihydroprostaglandin drugs, and 13,14-dihydro-15-ketoprostaglandin drugs; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone -Vinyl acetate copolymers or mixtures thereof.

DESCRIPTION OF THE INVENTION The present invention relates to a multilayer bead for pharmaceutical use, which has a polymer coating layer, wherein the drug is 15-keto prostaglandin drug, 13,14-dihydroprostaglandin drug, or 13,14- Dihydro-15-keto prostaglandin drug and the polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or a mixture thereof. More broadly, the present invention is applicable to fatty acid derivatives used as medicines and is described in US Patent No. 8,026,393, Formula I, the contents of which are expressly incorporated by reference. The present invention is based on the discovery that such bead and drug formulations unexpectedly stabilize the drug and prevent it from migrating out of the polymer drug coating. The present invention also relates to a pharmaceutical composition, which contains a plurality of the multi-layer beads and is used to treat gastrointestinal disorders, especially in children and the elderly.

It is known in the art that 15-keto prostaglandin drugs, 13,14-dihydroprostaglandin drugs, and 13,14-dihydro-15-keto prostaglandin drugs are effective in treating gastrointestinal disorders. These drugs, which are derivatives of fatty acids, are described in the published PCT application WO 2016/067620 and US Patent 6,414,016; the disclosure of which is incorporated into this case by reference. Representative examples of such drugs include, but are not limited to: (-)-7-[(2R, 4aR, 5R, 7aR) -2- (l, l-difluoropentyl) -2-hydroxy-6-oxo Octahydrocyclopenta [b] pyran-5-yl] heptanoic acid (lubiprostone); (-)-7-{(2R, 4aR, 5R, 7aR) -2-[(3S)- l, l-difluoro-3-methylpentyl] -2-hydroxy-6- pendant octahydrocyclopenta [b] pyran-5-yl} heptanoic acid (coproprostone )); (+)-Isopropyl (Z) -7-[(lR, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] heptane -5-enoic acid ester (isopropyl unoprostone); (Z) -7-[(lR, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-side Oxydecyl) cyclopentyl] hept-5-enoic acid; (-)-7-[(lR, 2R) -2- (4,4-difluoro-3-oxo-octyl) -5- Pendant cyclopentyl] heptanoic acid; and (E) -7-[(lR, 2R) -2- (4,4-difluoro-3- pendyloxyoctyl) -5- pendant cyclopentyl Yl] hept-2-enoic acid. The present invention provides novel formulations of 15-keto prostaglandin drugs, 13,14-dihydroprostaglandin drugs, and 13,14-dihydro-15-keto prostaglandin drugs. 15-keto prostaglandin medicine, 13,14-dihydroprostaglandin medicine and 13,14-dihydro-15-keto prostaglandin medicine include the medicine itself, the pharmaceutically acceptable salt of the medicine, or the medicine Metabolites or prodrugs, as well as isomers of this drug (including tautomers) and mixtures of isomers. Preferably, the drug is lubiprostone and includes its pharmaceutically acceptable salts, isomers, metabolites or prodrugs. For example, 15-hydroxylubiprostone is a metabolite of lubiprostone, described in US Patent No. 6,956,056. The amide prodrug system of lubiprostone is described in US Patent No. 7,064,148.

The present invention relates to a multi-layer bead for pharmaceutical use, which contains 15-keto prostaglandin medicine, 13,14-dihydroprostaglandin medicine, or 13,14-dihydro-15-keto prostaglandin medicine as active medicine Ingredients (API). FIG. 1 illustrates the multilayer bead of the present invention. In the multilayer bead of the present invention, there are: (a) a core particle [101]; (b) an optional barrier layer [102], which is coated on the surface of the core particle; (c) a polymer A drug coating layer [103], which is coated on the surface of the core particle, or when the barrier layer is present, it is coated on the surface of the barrier layer, wherein the polymer drug coating layer basically consists of the following: (i) a drug selected from the group consisting of: 15-keto prostaglandin drugs, 13,14-dihydroprostaglandin drugs, and 13,14-dihydro-15-keto prostaglandin drugs; and ( ii) A polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or mixtures thereof; (d) an optional sealing layer [104] coated on the On the surface of the polymer drug coating layer; and (e) optionally, one or more outer layers [105], which are outside the polymer drug coating layer, or when the sealing layer is present, it is on the sealing layer Outside. Those skilled in the art can adjust the number and composition of such layers, for example, to modify the release and stability curves of the beads and mask their taste. However, the outer layer shown in this case is preferred.

Multi-layer beads generally have a diameter or a maximum dimension of about 2000 to about 3000 microns along their longest axis. For example, the largest dimension is about 500 to about 1000 microns or the largest dimension is about 700 to about 950 microns. Like core particles, multi-layer beads are generally spherical or spheroid-like shapes, but may have another shape, such as, for example, an elongated shape or a rhombic shape. When used as a children's medicine, the diameter or longest axis of the multilayer beads of the present invention should meet the size requirements of the USFDA for administration to children or as a drug application formulation. For example, the target bead size is at most 2.5 mm, with no more than 10 percent change in this size, and the maximum size is 2.8 mm. See USFDA Guidance for Industry, "Size of Beads in Drug Products Labeled for Sprinkle", May 2012. The amount of drug present in the multilayer beads of the present invention may range from about 0.01 μg to about 0.2 μg, from about 0.02 μg to about 0.1 μg, or from about 0.04 μg to about 0.08 μg, although the amount within each bead It can be adapted to the therapeutically desired amount of drugs and the number of beads present in a specific pharmaceutical composition.

The core particles [101] can be any core particles used in the pharmaceutical field to make bead-like formulations. Spherical or quasi-spherical particles are generally used, but the core particles can be any shape that can be coated with the remaining layers of the multilayer bead of the present invention. The core particles may have a diameter or longest axis ranging from about 100-1,500 μm, about 200-700 μm, or about 350-500 μm. Exemplary core particles that can be used in the multilayer beads of the present invention are microcrystalline cellulose particles, silica particles, and sugar particles. Microcrystalline cellulose particles with a spherical shape and a range of diameters are sold under the Cellets® trade name. Cellets® 100 is spherical microcrystalline cellulose spheres with a particle size ranging from 100-200 μm, Cellets® 350 is spherical microcrystalline cellulose spheres with a particle size ranging from 350-500 μm, Cellets® 500 is a spherical microcrystalline cellulose sphere with a particle size in the range of 500-710 μm and Cellets® 1000 is a spherical microcrystalline cellulose sphere with a particle size in the range of 1000-1400 μm.

In the multilayer bead of the present invention, an optional barrier layer [102] can be coated on the surface of the core particle. The purpose of this barrier layer is to separate the polymer-coated layer [103] from the core particles [101], and to reduce or prevent contact between the drug and the core. As shown in Example 1a below, contact of the drug with the core particle [101] may cause the drug to degrade and lose the efficacy of the pharmaceutical formulation. The barrier layer is usually a polymeric layer. Any pharmaceutically acceptable polymer that performs the desired barrier layer function can be used. Preferably, the polymer is polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (PVP-VA or a mixture of these. A variety of standardized PVP and PVP-VA are commercially available, for example Said, Kollidon® 17PF and Kollidon® VA manufactured by BASF. Any commercially available, pharmaceutically acceptable PVP or PVP-VA or a combination thereof can be used for the polymer medium.

The 15-keto prostaglandin drugs, 13,14-dihydroprostaglandin drugs, or 13,14-dihydro-15-ketoprostaglandin drugs that are APIs in the multilayer beads of the present invention are located in the polymer Drug coating layer [103]. The polymer coating layer according to the present invention basically consists of the following: (i) a drug selected from the group consisting of 15-keto prostaglandin drugs, 13,14-dihydroprostaglandin drugs, and 13, 14-dihydro-15-ketoprostaglandin; and (ii) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or mixtures thereof. In a polymer-coated layer [103], the drug may be present as an amorphous solid or a crystalline solid, or the drug may be molecularly dissolved in the solid excipient medium. The drug has a relative drug-to-polymer ratio of 1 part drug per 0.2 parts polymer up to 200 parts polymer, 400 parts polymer, 500 parts polymer, 1,000 parts polymer, and The range of about 1 part of 10,000 parts of polymer is present in the polymer coating layer.

The polymer drug coating [103] can be a simple blend of the drug and the polymer or a solid dispersion of the drug in the polymer. A solid dispersion is a solid composition having at least two components, one of which is dispersed in a medium composed of the other component. For example, the drug is dispersed as a solid in a polymerization medium. The solid dispersion used in this case also includes a solid solution in which one component is molecularly dissolved in a solid medium composed of another component. For example, the drug is molecularly dissolved in the excipient medium.

The polymer drug coating layer [103] is basically composed of the drug and the polymer. This layer may-like the remaining layers of the multilayer bead of the present invention-contain processing aids or excipients, such as those discussed below. The polymer drug-coated layer [103] should not contain components that would allow the drug to migrate within the layer so that the drug may leach or degrade from the remaining layers of the multi-layer bead. Such polymer-coated mixtures do not contain excipients that may affect the stability of the drug in the polymer-coated layer, so that the drug retains its therapeutic effect. It has been found that the polymer drug-coated layer and the multilayer beads of the present invention are particularly stable even under stress stability test conditions. The multilayer beads of the present invention retain at least 75-80% of the pharmaceutical efficacy or potency of the drug after being exposed to storage conditions of 55 ° C for 10 days. Thus, the multilayer bead of the present invention maintains a state or condition suitable for administration to a patient, and is therapeutically effective without potentially interfering with deterioration products.

In the multilayer beads of the present invention, an optional sealing layer [104] may be coated on the surface of the polymer drug-coated layer [103]. Similar to the barrier layer [102], when the sealing layer is present, the purpose of the sealing layer is to separate the polymer-coated layer [103] and the outer layer (s) [105], and to reduce or prevent the drug from the Multilayer bead leaching. As shown in Example 1 below, contact of the drug with the outer layer polymer may cause the drug to degrade and lose the efficacy of the pharmaceutical formulation. The sealing layer is usually a polymeric layer. Any pharmaceutically acceptable polymer that performs the desired sealing layer function can be used. Exemplary polymers are polyvinylpyrrolidone (PVP), vinylpyrrolidone-vinyl acetate copolymer (PVP-VA), or mixtures thereof. Various standardized PVP and PVP-VA are commercially available, for example, Kollidon® 17PF and Kollidon® VA manufactured by BASF. Any commercially available, pharmaceutically acceptable PVP or PVP-VA or a combination thereof can be used for the polymer medium.

In the multi-layer beads of the present invention, the same polymer may constitute the barrier layer [102], the polymer coating layer [103] and the sealing layer [104], when these are present. In such multi-layer beads, the polymer in all three such layers may be polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer, or a mixture thereof. In fact, the barrier layer [102] and the sealing layer [104] sandwich the polymer drug coating layer [104] using the same polymer or polymer mixture. If other layers are incorporated into the multilayer beads of the present invention, this combination of barrier layer [102] / polymer drug coating layer [103] / sealing layer [104] can be maintained to achieve the purpose of these layers and the multilayer beads Stability.

The multilayer beads of the present invention may optionally contain one or more outer layers [105] to modify their release and / or odor properties, reduce water and oxygen penetration, and / or provide mechanical properties to the particles to withstand fracture or Cutting. Such coatings are known in the art. For example, coatings that mask odors or prevent neutral dissolution at pH but allow rapid dissolution in an acidic environment can be used to prevent dissolution or disintegration of multilayer beads until after they are administered as part of a pharmaceutical composition Reach the stomach environment. Such polymers, for example, are insoluble in the pH range of 6 to 8 and soluble in the pH range of 1 to 5, or insoluble in the pH range of 5 to 8. The pH is soluble in the range of 1 to 4. A wide range of copolymer systems based on methacrylic acid and methyl methacrylate systems are commercially available, such as the EUDRAGIT® polymer sold by Evonik. In the multilayer bead of the present invention, the outer layer contains a copolymer containing butyl methacrylate. Preferably, EUDRAGIT® E100—a copolymer of aminoethyl dimethyl methacrylate, butyl methacrylate, and methyl methacrylate—is used as the outer layer.

As discussed above, the layers of the multilayer beads may contain additives for easy coating, which are selected from pharmaceutically acceptable excipients known in the art. For example, one or more of these layers may contain plasticizers and lubricants, such as PEGs and polyethylene glycol. Plasticizers include, for example, glycerin, acetyl tributyl citrate, polyethylene glycol, acetyl triethyl citrate, polyethylene glycol monomethyl ether, castor oil propylene glycol, diethyl acetyl Monoglyceride, sorbitol desorbed sorbitol solution, dibutyl sebacate, diethyl phthalate, triacetin, tributyl citrate and triethyl citrate. Furthermore, each layer can be sprinkled with antistatic agents or static elimination agents, such as talc and silica. Such materials are used in a manner and amount known in the art, as they do not substantially interfere with the stability of the drug and the multilayer beads, and preferably improve the stability of the drug and prevent it from migrating to the polymerization Things outside the medicine layer.

In a preferred embodiment, in the multilayer bead of the present invention, there are: (a) a core particle [101]; (b) a barrier layer [102], which is coated on the surface of the core particle; ( c) A polymer drug coating layer [103], which is coated on the surface of the core particle, or when the barrier layer is present, it is coated on the surface of the barrier layer, wherein the polymer drug coating layer is substantially It consists of the following: (i) One medicine, selected from the group consisting of: 15-keto prostaglandin medicine, 13,14-dihydroprostaglandin medicine, and 13,14-dihydro-15-keto prostate Plain medicine; and (ii) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or mixtures thereof; (d) a sealing layer [104], which is coated Covering the surface of the polymer drug coating layer; and (e) one or more outer layers [105] which are outside the polymer drug coating layer or when the sealing layer is present, it is on the sealing layer outside. This specific example may include various other aspects of the multilayer bead of the present invention discussed above. This medicine may be lubiprostone (or a pharmaceutically acceptable salt, isomer, metabolite, or prodrug thereof).

The multi-layer beads of the present invention are prepared using coating techniques known in the art, such as fluidized bed coating devices, which sequentially coat the core particles with the specified layers. The layers can be applied sequentially as a solution or dispersion of their components, followed by drying to remove the solvent before applying the next coating. Individual layers are sprayed with solvents. An exemplary solvent used for spraying is acetone. The spraying is carried out at a temperature not exceeding 30 ° C. The coating is dried at a temperature not exceeding 45 ° C.

The invention also relates to a pharmaceutical composition, which comprises a plurality of multilayer beads according to the invention and a pharmaceutically acceptable excipient. The pharmaceutical composition of the present invention can be an oral dosage form or a multi-layer bead package that can be opened and administered to the beads. In the pharmaceutical composition of the present invention, the plurality of multi-layer beads may be contained in a capsule, sachet or pouch.

The invention also relates to solid formulations of drugs in polymers. The solid formulation of the drug in the polymer may be a simple blend of the drug and the polymer or a solid dispersion of the drug in the polymer. The solid formulation of the drug according to the present invention in a polymer is a solid dispersion consisting essentially of (a) a drug, selected from the group consisting of: 15-ketoprostaglandin, 13,14- Dihydroprostaglandin, and 13,14-dihydro-15-ketoprostaglandin; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer Thing or its mixture. Another solid formulation of the drug according to the present invention in the polymer is a blend consisting essentially of: (a) a drug selected from the group consisting of: 15-ketoprostaglandin, 13, 14-dihydroprostaglandin, and 13,14-dihydro-15-ketoprostaglandin; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate Ester copolymer or its mixture.

The solid formulation of the drug according to the invention in the polymer may be in the form of particles and consist essentially of the following: (a) a drug selected from the group consisting of: 15-ketoprostaglandin, 13,14- Dihydroprostaglandin, and 13,14-dihydro-15-ketoprostaglandin; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer Thing or its mixture. Those skilled in the art will be able to select the appropriate particle size depending on the mode of administration, the pharmaceutical formulation containing the solid formulation, and the manufacturing parameters. As an upper limit, the particles themselves can be as large as the size of the lozenge.

The present invention also relates to a pharmaceutical composition, which contains a solid formulation of a drug in a polymer combined with a pharmaceutically acceptable excipient. In such pharmaceutical formulations, the solid formulation of the drug in the polymer may be in the form of particles, basically consisting of: (a) a drug, selected from the group consisting of: 15-keto prostaglandin drugs, 13,14-dihydroprostaglandin drugs, and 13,14-dihydro-15-ketoprostaglandin drugs; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone- Vinyl acetate copolymer or its mixture. The solid formulation of the drug in the polymer can form the core of a multi-layer bead or a single dosage form, both with one or more of the layers discussed above. The pharmaceutical composition may contain a plurality of multilayer beads.

The pharmaceutical composition of the present invention can be prepared by a conventional method in the field of pharmaceutical formulation, for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990), the contents of which are incorporated by reference. Into. In the dosage form, the layers other than the polymer coating layer of the beads, and the multilayer beads themselves can be blended with at least one pharmaceutically acceptable excipient, for example, sodium citrate or phosphoric acid Dicalcium or (a) fillers or extenders, for example, starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binding agents, for example, cellulose derivatives, Starch, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, (c) humectants, for example, for example, glycerin, (d) disintegrants, for example, for example, agar, calcium carbonate, Potato or cassava starch, alginic acid, croscarmellose sodium, complex silicate, and sodium carbonate, (e) solution retarder, for example, paraffin, (f) absorption accelerator, For example, for example, a quaternary ammonium compound, (g) a wetting agent, for example, for example, cetyl alcohol, and glycerol monostearate, magnesium stearate, etc., (h) an adsorbent, for example, For example, kaolin and bentonite, and (i) lubricants, such as, for example, talc, stearin Calcium, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, etc. or mixture thereof. In the case of capsules, lozenges, and pills, the dosage form may also contain buffering agents. Acceptable excipients may also be present between adjacent layers of multilayer beads. For example, the excipient may be present between the outer layer and the sealing layer, between the sealing layer and the polymer coating layer, between the polymer coating layer and the barrier layer, between the barrier layer and the core, or the like combination.

Pharmaceutically acceptable adjuvants known in the field of pharmaceutical formulation can also be used in the pharmaceutical composition of the present invention. These include but are not limited to preservatives, wetting agents, suspending agents, sweeteners, flavoring agents, perfuming agents, emulsifying agents, and dispersing agents. By including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, etc. can ensure the prevention of the action of microorganisms. It may also be necessary to include isotonic agents, for example, sugar, sodium chloride, and the like. If necessary, the pharmaceutical composition of the present invention may also contain a small amount of auxiliary substances, such as wetting agents or emulsifiers, pH buffers, antioxidants, etc., for example, citric acid, sorbitan monolaurate , Triethanolamine oleate, butylated hydroxytoluene, etc.

The pharmaceutical composition of the present invention may be an oral dosage form containing a plurality of multi-layer beads and other excipients to allow transportation, storage and distribution. The dosage form may comprise beads, either in free-flowing form or in the form of a lozenge, such as a rapidly disintegrating lozenge that releases the multilayer bead. Such rapidly disintegrating lozenges, for example, may include disintegrating agents in addition to the multilayer beads. The pharmaceutical composition of the present invention may also be a solid dosage form, for example, as illustrated in the examples below, for example, a lozenge or hard capsule prepared by a solid solution of lubiprostone and PVP or PVP-PA together . Such solid dosage forms, for example, can be made to release at least 70% within 30 minutes when measured with a USP Type 2 dissolution device at 37 ° C and 200 rpm in 810 ml of neutral water and 90 ml of 1N HCl The amount of medicine contained in the dosage form.

Solid dosage forms for oral administration, such as lozenges, are well known in the art and can be prepared by any method well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa. (18th ed. 1990). Lozenges can be made by optionally compressing or molding with one or more excipients. Compressed lozenges can be in free-flowing form by compression in a suitable machine, such as powder or granular active ingredients, optionally with excipients such as binding agents, lubricants, inert diluents, preservatives, surface active Agent or dispersant mixed to prepare. Molded lozenges can be made by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine. Lozenges can be optionally coated or scored and can be formulated to provide slow or controlled release of the active ingredient therein. The capsule dosage form of the present invention may be a hard capsule, and is generally made of animal-derived gelatin or plant-derived hydroxypropyl methyl cellulose (HPMC). The size of the capsule used in the oral dosage form of the present invention may be any size sufficient to contain its components. For example, the capsule may be of size 5, 4, 3, 2, 1, 0, 0E, 00, 000, 13, 12, 12, el, 11, 10, 7, or Su07. The capsule is filled using any suitable technique known in the art.

A plurality of multi-layer beads in the pharmaceutical composition are combined to contain a therapeutically effective amount of the drug for administration to patients in need thereof. The multi-layered beads can be packaged for administration (or by another suitable administration tool, such as a measuring spoon). The dose of the plurality of multilayer beads present in the pharmaceutical composition of the present invention may range from about 1 μg to about 75 μg, from about 4 μg to about 50 μg, or from about 8 μg to about 25 μg or In particular, it can be 8, 12, 16 or 24 μg. The unit dose of the drug is about 1 μg to about 1,500 μg, for example, about 1 μg to about 100 μg, for example, 8 μg to about 72 μg. The pharmaceutical composition of the present invention includes unit dosage forms, for example, 8, 12, 16, 24, 48, or 72 μg lubiprostone (or a pharmaceutically acceptable salt, isomer, metabolite, or prodrug thereof) .

The present invention also relates to a method of treating gastrointestinal disorders, the method comprising the step of orally administering a therapeutically effective amount of multilayer beads in the pharmaceutical composition of the present invention to a patient in need thereof. Accordingly, the present invention relates to the use of the pharmaceutical composition of the present invention to treat gastrointestinal disorders. One such gastrointestinal disorder is constipation, and other gastrointestinal disorders include but are not limited to those related to dysfunctional type 2 chloride channel, including the following disorders: chronic idiopathic constipation, opioid-induced constipation, and intestinal mania The accompanying constipation. The gastrointestinal disorder being treated can also be an inflammatory bowel disease, for example, for example, ulcerative colitis or Crohn's disease.

It is envisaged that the formulations according to the present invention can be administered to treat gastrointestinal disorders that have been approved or that various national regulatory agencies may approve the administration of lubiprostone in the future. Such indications include but are not limited to: (a) treatment of chronic idiopathic constipation (CIC) in adults; (b) treatment of adult opioid-induced constipation (OIC) with chronic, non-cancer pain; (c) in 6 Treatment of functional constipation in children (PFC) in patients up to 17 years of age (approval pending in the US FDA at the time of application for this application); -C). It is further envisaged that the beaded formulations according to the present invention will be helpful when administered to individuals who have difficulty swallowing or have difficulty swallowing conventional tablets or capsules, especially children or individuals. Dysphagia can occur in various diseases, for example, for example, post-polio syndrome, multiple sclerosis, muscular dystrophy, Parkinson's disease, polymyositis, dermatomyositis, esophageal spasm, and scleroderma.

"Treatment of" or "treating a gastrointestinal disorder" includes any form of treatment control, such as prevention, care, symptom relief, symptom relief, and progression of cessation. The treatment may be "long-term", involving administration of the pharmaceutical composition of the invention for a long period of time, for at least two weeks, at least three weeks, at least one month, at least two months, or at least six months to one year or more. The pharmaceutical composition can be administered daily or at intervals of one to several days throughout the treatment period and one or more times per day.

"Therapeutically effective amount of medicine" refers to the amount of medicine that causes a therapeutically beneficial response to patients in need thereof. The patient is usually a human patient, but may also include other mammals, such as horses under veterinary care, companion animals (dogs or cats), livestock, and zoo animals. The "therapeutically effective amount" can be determined based on age, weight, the condition of the patient to be treated, the desired treatment effect, the administration route, and the treatment period. An exemplary therapeutically effective amount of lubiprostone (or a pharmaceutically acceptable salt, isomer, metabolite, or prodrug thereof) can be, for example, once, twice, or three times per day 4, 8, 12, or 24 μg, or 48 μg once or twice a day.

The treatment method or use of the pharmaceutical composition may include sprinkling the multi-layer beads of the pharmaceutical formulation into water or onto soft food, and causing the patient to swallow the water or soft food with the multi-layer beads. This is particularly useful when treating gastrointestinal disorders in children or elderly patients and in individuals aged 0-17 years and / or individuals with dysphagia. The multilayer beads can also be sprinkled with water (or another suitable beverage), which can be stirred or shaken before swallowing to form a multilayer bead suspension. Soft foods require minimal or no chewing, and include but are not limited to foods such as applesauce, yogurt, ice cream, cheese, baby food, infant formula, etc. Preferably, multiple layers of beads can be sprinkled into water and / or applesauce. The multilayer beads of the present invention can be made to resist the release of the drug for at least about one to fifteen minutes after exposure to water or soft food. The multilayer particles and pharmaceutical composition of the present invention then delay or prevent drug release into the neutral suspension carrier and into the body before reaching the stomach. Compared with previous gel capsule formulations, the pharmaceutical composition of the present invention containing the multi-layer bead reduces adverse events related to nausea and vomiting. Example materials

The following materials are used in the examples described below:

Colloidal silica: Aerosil® R972 Pharma, high purity, amorphous, anhydrous, hydrophobic colloidal silica excipient, available from Evonik Industries.

Microcrystalline cellulose particles (MCC spheres): Cellets® 350 spherical microcrystalline cellulose spheres with particle sizes in the range of 350-500 μm, available from Glatt Pharmaceutical Services.

Dibutyl sebacate (DBS), a plasticizer, which is an oil (not a solid material), is available from Aldrich.

Eudragit E100, an ionic copolymer based on methacrylic acid and methyl methacrylate, manufactured by Evonik Nutrition & Care GmbH.

Lubiprostone, the active pharmaceutical ingredient (API).

Polyethylene glycol, with a molecular weight of about 6000 ear swallows, PEG-6000, is available from TCI Chemicals.

Polyvinylpyrrolidone (PVP), also known as Povidone (Povidone), Kollidon® 17PF USP, is manufactured by BASF.

Polyvinylpyrrolidone-vinyl acetate copolymer (PVP-VA), also known as copovidone (Copovidone), Kollidon® VA64 USP, manufactured by BASF.

Talc and lubricants are available from BRENNTAG.

Lactose, lactose monohydrate USP / JP, is available from Maruishi Pharmaceutical.

Mannitol: PEARLITOL® 200 SD, manufactured by Roquette.

Glucose, dextrose USP / glucose JP, is available from Wako Pure Chemical Industries.

Hydroxypropyl cellulose (HPC), USP / JP, available from Nippon Soda.

Hydroxypropyl methylcellulose (HPMC), also known as Hypromellose USP / JP, is available from Sigma Aldrich.

Microcrystalline cellulose powder (MCC powder): CEOLUS® UF-702, manufactured by Asahi Kasei.

Corn starch, USP / JP, is available from Wako Pure Chemical Industries.

Magnesium aluminate metasilicate (MgAMS), available from Tomita Pharmaceutical. Example 1A : Lubiprostone- excipient contact stability study

Various excipients and lubiprostone were used to prepare test samples for the study at a ratio of approximately 50:50. The prepared mixture was then placed under accelerated stress stabilization conditions at 55 ° C for 10 days. After 10 days, the samples were analyzed by a suitable HPLC method to determine the sample (the remaining amount of lubiprostone) and impurities due to the degradation of lubiprostone. The results are shown in Table 1A. Table 1A Example 1B : Lubiprostone- excipient contact stability study ( solid solution)

Additional test samples for the study were prepared by blending various excipients and lubiprostone in a ratio of about 50:50 to about 99: 1. The solid solution is prepared by mixing lubiprostone / MeCN and excipient / MeCN, combining these mixtures and then removing the solvent by suction drying. The prepared mixture was then placed under accelerated stress stabilization conditions at 55 ° C for 10 days. After 10 days, the samples were analyzed by HPLC method to determine the remaining amount of lubiprostone and impurities due to degradation of lubiprostone.

The results of the 50:50 solution are shown in Table 1B, where the stability of the solid solution of lubiprostone and PVP, PVP-VA and DBS is relatively high. The latter (DBS) is an oil, and is used as a conventional plasticizer for coating films on granules and beads. It may be useful as a stabilizer in some lubiprostone bead formulations, but it is not a preferred component.

Compared to the 50:50 solid solution, the results of the 99: 1 solid solution show that the lubiprostone and PVP and PVP-VA solid solutions have relatively high stability. Without being limited to any particular explanation, it is believed that the lubiprostone molecule is surrounded by a relatively increased number of excipient molecules that enhance stability. Table 1B Example 1C : Lubiprostone- excipient contact stability study ( mechanical mixed powder)

Test samples were prepared by directly (mechanically) mixing various excipients with lubiprostone in approximately 50:50 and 99: 1 ratios. The mechanical mixing of lubiprostone and excipients is carried out by blending these using a conventional mill. The prepared mixture was then placed under accelerated stress stabilization conditions at 55 ° C for 10 days. After 10 days, the samples were analyzed by HPLC to determine the remaining amount of lubiprostone and impurities due to degradation of lubiprostone. The results are shown in Table 1C. The observed increase in the stability of lubiprostone due to mechanically mixed powders was only seen in PVP and PVP-VA. However, this increase in stability was not as great as that observed for solid solutions in Example 1B. Without being limited to any particular interpretation, it is believed that this result is due to relatively little complete mixing. Table 1C Example 2 : Lubiprostone / polymer layer stability test

The lubiprostone / polymer solution was made up to 10 wt% solids in acetone (HPLC grade, EMD). Approximately 2.5 g of each polymer solution was transferred to an aluminum pan (~ 10 cm diameter) and dried at 40 ° C for at least 4 hours to form a drug / polymer layer with a thickness of approximately 100 μm. Visually check the membrane integrity of the resulting membrane. All films were then placed in a forced air convection oven at 55 ° C and the appearance change was checked after 10 days. The appearance of each individual drug / polymer is summarized in Table 2. Table 2 Example 3 : Preparation of multilayer bead formulation

Using the bottom spray fluidized bed (VFC-LAB Micro Flo-coater) coating method, spherical microcrystalline cellulose particles (Cellets® 350) were sequentially coated with a polymer barrier (PVP or PVP- VA) layer, Lubiprostone (Lubi) / polymer layer, seal coat (PVP or PVP-VA) and waterproof outer layer (polymethacrylate Eudragit E 100). Table 3 reports the polymer, spray solution concentration, solvent system, and method parameters, including bed temperature (T _bed ), solution feed rate (Q), and nozzle atomization pressure (P). The coating weight is calculated by dividing the weight of the polymer layer by the total product weight (ie, the weight of the polymer layer and the substrate). After coating the layers, a forced tray convection oven was subjected to a secondary tray drying step overnight at 40 ° C to remove residual acetone. table 3 * Barrier coating weight = 20% and seal coating weight = 25% Example 4 : Multi-layer bead formulation and particle size distribution determination

The coated beads were prepared as illustrated in Example 3. The sequential particle size of the beads before and after coating was determined by laser diffraction using Malvern Mastersizer 300 in Aero S units (Malvern Instruments). The diameters of D10, D50 and D90 are used to characterize the particle size distribution of the powder. For example, the D50 diameter is the diameter of 50% of the sample mass composed of smaller particles. The particle size distribution before and after each coating step was measured via laser diffraction. The results are shown in Table 4, the following abbreviations: Cellets = Cellets® 350, Lubi = Lubiprostone and E = Eudragit® E100. Table 4

As shown in Table 4, the particle size of the final product is approximately less than 1 mm, which is a suitable size for oral suspension administration in water or for sprinkling on soft foods. Example 5 : Dissolution test

The two-stage dissolution test (ie, neutral pH → stomach pH) was performed on the coated beads prepared as described in Example 3 using Distek's 2100C model USP Type 2 dissolution device to simulate the drug delivery process, Preheat the neutral dissolution medium (HPLC grade water with 1% Kolliphor RH40, BASF) to 37.0 ° C. All experiments were repeated twice. The analysis of the samples was performed using HPLC-MS. All three formulations showed negligible drug release after shaking in a neutral dissolution medium for 1 hour, while the drug was released almost immediately after adding 1N HCl to the medium. This indicates that the multi-layer beads are not only insoluble in neutral pH water, but also have minimal water permeability under such conditions. Once the surrounding pH decreases to the stomach pH, they dissolve quickly and release the drug into the medium. Example 6- Method for preparing multilayer beads

The following steps are used to prepare other batches of multilayer beads of the present invention: (a) Load the required amount of microcrystalline cellulose beads in a fluidized bed coater; (b) Dissolve PVP-VA in Prepare a primer solution in acetone and prepare a PEG 6000 aqueous solution; (c) Add talc and mix the solution from step (b) with talc; (d) Spray the coating solution from step (c); (e) Use The coated beads are dried; (f) The beads are further dried to remove the solvent; (g) The beads are loaded in a fluidized bed coater; (h) The required amount of Lubiprostone is placed in the acetone solution of the previously prepared PVP-VA, and PEG 6000 and talc are added (i) spray the beads with the solution from step (h); (j) after the second coating Drying the beads; (k) further drying the beads to remove the solvent; (l) loading the beads in a fluidized bed coater; (m) preparing PVP-VA in acetone Seal the coating solution and prepare PEG 6000 solution and mix with talc (n) spray the beads with the solution from step (m); (o) dry the beads after the third coating; (p) further Make the beads Drying to remove the solvent; (q) loading the beads in a fluidized bed coater; (r) mixing the amine methacrylate / acetone solution with PEG 6000 and talc to prepare a coating solution (s ) Spraying the beads with the solution from step (r); (t) drying the beads after the fourth coating; (u) further drying the beads to remove the solvent; and (v) Sort the beads to remove aggregates and particles.

An exemplary composition of the multilayer bead of the present invention is shown in Table 6. The particle size test using laser diffraction shows that the D90 particle size is 0.752 mm. Table 6 * Used as a solvent and removed during drying Example 7- Method for preparing multilayer beads

Table 7 shows another exemplary composition of the multilayer beads of the present invention. Table 7 Example 8- Bead stability and dissolution

The multilayer beads of the present invention are tested for stability under stress conditions. The beads were kept in a glass vial at 55 ° C for 10 days to determine the stability. These beads were subjected to a two-stage dissolution test (ie, neutral pH → stomach pH). The dissolution test was carried out as indicated by the Paddle method (apparatus 2), dissolved at 37 ° C (USP <711>) in HCO-40: polyethylene glycol 40 hydrogenated castor oil medium (kolliphor RH40 (BASF)) . Table 8 shows the remaining lubiprostone portion of lubiprostone beads prepared as described in Example 7 and the appearance and dissolution properties of related degrading substances. The amount of lubiprostone and related degrading substances was analyzed by HPLC. The criteria for passing the dissolution test are as follows: Phase 1 target-not more than 20% of the labeled amount is released in water with surfactant (1% HCO-40) within 30 mins; Phase 2 target-not less than 60% The indicated amount of (Q) is released in 0.1 N HCl with surfactant (1% HCO-40) within 60 mins. Table 8 Example 9- Pharmaceutical composition: Zazhu capsule

The multilayer beads of the present invention were mixed with 0.5 wt% talc. The size 0 hydroxypropyl methylcellulose blue / white bead beads capsules were filled with the multilayer bead and talc mixture. Example 10- Dissolution test: Sprinkle beads capsules

The two-stage dissolution test (ie, neutral pH → stomach pH, as described above) was carried out on a bead containing Lubiprostone beads prepared as above. The multilayer beads from the capsule were sprinkled into the dissolution medium and the dissolution test was carried out as described in Example 8. Figure 2 shows the dissolution profile of little or no drug release in a neutral aqueous environment, while the entire remaining drug is released in an acidic environment (like the stomach). Example 11- Stability and dissolution of Zazhu capsules

Beads in carboxypropyl methylcellulose capsules prepared as described above-with 24 µg lubiprostone and multilayer beads-were used to test stability and dissolution. The stability study was conducted using HDPE screw cap bottles with desiccant. The stability data at 25ºC / 60% RH and 40ºC / 75% RH for up to 3 months are shown in Tables 9 and 10. As shown below, the batch shows good stability. Table 9: Stability test at 25ºC / 60% RH Table 10: Stability test at 40ºC / 75% RH Example 12- Stability of sprinkle beads capsules and applesauce

An in vitro test was conducted to establish the chemical compatibility of the drug lubiprostone in a carrier intended for administration (applesauce). Combine sprinkle beads from one capsule (beads containing 24 µg lubiprostone) with applesauce, TREE TOP applesauce (without added sugar), 5 g (on a teaspoon). The beads were maintained at room temperature and samples were taken at 0, 5, 10, and 20 min.

After sprinkling the capsule contents on the applesauce, the beads are recovered by decanting and rinsing (with water), and then the API content of the beads (sample) is determined. The results are shown in Table 11, which indicates that-when mixed with applesauce for up to 20 mins-the good chemical compatibility of the beads (although patients are expected to consume within the first 5 minutes). This result also confirms that the functional coating (acid-soluble layer) prevents API from oozing out of the bead formulation when sprinkled on applesauce. Table 11.

The present invention includes all specific examples and variations substantially as described above with reference to the embodiments and drawings. Although various specific examples of the present invention have been disclosed in this case, according to the common knowledge of those skilled in the art, adjustments and modifications can be made within the scope of the present invention.

101‧‧‧Core particles

102‧‧‧ barrier layer

103‧‧‧ Polymer coating

104‧‧‧Sealing layer

105‧‧‧Outer

FIG. 1 illustrates the multilayer bead of the present invention.

2 shows the dissolution curve described in Example 10.

Claims (70)

A multi-layer bead for pharmaceutical use, comprising: (a) a core particle; (b) an optional barrier layer coated on the surface of the core particle; (c) a polymer drug-coated layer ( drug-in-polymer layer), which is coated on the surface of the core particle, or when the barrier layer is present, it is coated on the surface of the barrier layer, wherein the polymer-coated layer consists essentially of : (I) a medicine selected from the group consisting of: 15-keto prostaglandin medicine, 13,14-dihydroprostaglandin medicine, and 13,14-dihydro-15-keto prostaglandin medicine; And (ii) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or mixtures thereof; (d) an optional sealing layer coated on the On the surface of the polymer drug coating layer; and (e) optionally one or more outer layers, which are outside the polymer drug coating layer, or when the sealing layer is present, it is outside the sealing layer. As in the multilayer bead of claim 1, wherein the drug is selected from the group consisting of: (-)-7-[(2R, 4aR, 5R, 7aR) -2- (l, l-difluoropentyl) -2-hydroxy-6- pendant octahydrocyclopenta [b] pyran-5-yl] heptanoic acid (lubiprostone); (-)-7-{(2R, 4aR , 5R, 7aR) -2-[(3S) -l, l-difluoro-3-methylpentyl] -2-hydroxy-6- pendant octahydrocyclopenta [b] pyran- 5-yl} heptanoic acid (cobiprostone); (+)-isopropyl (Z) -7-[(lR, 2R, 3R, 5S) -3,5-dihydroxy-2- ( 3-oxodecyl) cyclopentyl] hept-5-enoate (isopropyl unoprostone); (Z) -7-[(lR, 2R, 3R, 5S)- 3,5-dihydroxy-2- (3-oxodecyl) cyclopentyl] hept-5-enoic acid; (-)-7-[(lR, 2R) -2- (4,4-di Fluoro-3-oxooxyoctyl) -5-oxocyclopentyl] heptanoic acid; and (E) -7-[(lR, 2R) -2- (4,4-difluoro-3-side Oxyoctyl) -5- pendant cyclopentyl] hept-2-enoic acid. The multi-layer bead according to claim 1 or 2, wherein the drug is lubiprostone. The multilayer bead of any one of 2 or 3, wherein the polymer coating layer is a blend of the drug and the polymer or a solid dispersion of the drug in the polymer. The multilayer beads of any one of 2, 3, or 4, wherein the amount of drug present in the multilayer beads is between about 0.01 μg to about 0.2 μg, from about 0.02 μg to about 0.1 μg, or from about 0.04 μg To a range of about 0.08 μg. The multi-layer bead as claimed in any one of claims 1 to 5, wherein the drug is in a relative portion of drug to polymer ranging from 1 part drug per 0.2 parts polymer up to 200 parts polymer per 400 parts polymer The range of substance, polymer per 500 parts, polymer per 1,000 parts, and approximately 1 drug per 10,000 parts of polymer is present in the polymer drug coating layer. The multilayer bead as claimed in claim 4, wherein the polymer drug coating layer is a solid dispersion of the drug in the polymer. The multilayer bead according to any one of claims 1 to 7, wherein the core particles are selected from the group consisting of microcrystalline cellulose particles, silica particles, and sugar particles. The multilayer bead according to any one of claims 1 to 8, which has a barrier layer and the barrier layer is a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-acetic acid Vinyl ester copolymer or its mixture. The multilayer bead according to any one of claims 1 to 9, which has a sealing layer and the sealing layer is a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-acetic acid Vinyl ester copolymer or its mixture. The multilayer bead according to any one of claims 1 to 10, which has one or more outer external layers selected from the group consisting of methacrylate-based polymers. A pharmaceutical composition comprising a plurality of multilayer beads as claimed in any one of claims 1 to 11 and a pharmaceutical excipient. The pharmaceutical composition according to claim 12, wherein the plurality of multilayer beads are contained in a capsule, sachet or pouch. The pharmaceutical composition according to claim 12, wherein the plurality of multi-layer beads are combined to form a unit dose of the drug, preferably between about 1 μg to about 1,500 μg, from about 1 μg to about 75 μg, from about 4 μg It may range from about 50 μg, or from about 8 μg to about 25 μg, or in particular may be 4, 12, 8, 16 or 24 μg. A method for treating a gastrointestinal disorder, the method comprising the step of orally administering a therapeutically effective amount of multi-layer beads in a pharmaceutical composition as claimed in claim 12, 13 or 14 to a patient in need thereof. The method of claim 15, the method comprising sprinkling the pharmaceutical composition in water or on soft food, and causing the patient to swallow the water or food containing the multi-layered beads. The method of claim 15 or 16, wherein the gastrointestinal disorder is related to a dysfunctional type 2 chloride channel, including a disorder selected from the group consisting of chronic idiopathic constipation, opioid-induced constipation, and Constipation associated with intestinal irritability. Use of a pharmaceutical composition according to any one of claims 12, 13 or 14 for the treatment of a gastrointestinal disorder. Use of the pharmaceutical composition according to claim 18, wherein the gastrointestinal disorder related to dysfunctional type 2 chloride channel includes a disorder selected from the group consisting of chronic idiopathic constipation, opioid-induced constipation, Constipation associated with intestinal mania and functional constipation in children. A solid dispersion of a drug in a polymer, which basically consists of the following: (a) A drug selected from the group consisting of: 15-keto prostaglandin drug, 13,14-dihydroprostaglandin Medicine, and 13,14-dihydro-15-keto prostaglandin medicine; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or Wait for the mixture. The solid dispersion according to claim 20, wherein the drug is selected from the group consisting of: (-)-7-[(2R, 4aR, 5R, 7aR) -2- (l, l-difluoropentyl) -2-hydroxy-6- pendant octahydrocyclopenta [b] pyran-5-yl] heptanoic acid (lubiprostone); (-)-7-{(2R, 4aR, 5R, 7aR) -2-[(3S) -l, l-difluoro-3-methylpentyl] -2-hydroxy-6-oxooctahydrocyclopenta [b] pyran-5-yl } Heptanoic acid (coprostol); (+)-isopropyl (Z) -7-[(lR, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-oxodecane (Yl) cyclopentyl] hept-5-enoate (isopropyl unoprostone); (Z) -7-[(lR, 2R, 3R, 5S) -3,5-dihydroxy-2- ( 3-oxodecyl) cyclopentyl] hept-5-enoic acid; (-)-7-[(lR, 2R) -2- (4,4-difluoro-3-oxooctyl) -5-oxo-cyclopentyl] heptanoic acid; and (E) -7-[(lR, 2R) -2- (4,4-difluoro-3-oxo-octyl) -5-oxo Cyclopentyl] hept-2-enoic acid. The solid dispersion of claim 21, wherein the drug is lubiprostone. A solid dispersion as claimed in any one of claims 20 to 22, wherein the drug is in a relative portion of drug to polymer ranging from 1 part drug per 0.2 parts polymer up to 200 parts polymer per 400 parts polymer There is a range of substances, every 500 parts of polymer, every 1,000 parts of polymer, and about 1 part of medicine per 10,000 parts of polymer. A pharmaceutical composition comprising the solid dispersion according to any one of claims 20 to 23 and a pharmaceutically acceptable excipient, wherein the medicine is present in a pharmaceutically effective amount to treat a gastrointestinal disorder. A solid formulation of a drug in a polymer, which basically consists of the following: (a) A drug, selected from the group consisting of: 15-keto prostaglandin drugs, 13,14-dihydroprostaglandin drugs, And 13,14-dihydro-15-keto prostaglandin; and (b) a polymer selected from the group consisting of polyvinylpyrrolidone, vinylpyrrolidone-vinyl acetate copolymer or mixtures thereof . The solid formulation of claim 25, wherein the drug is selected from the group consisting of: (-)-7-[(2R, 4aR, 5R, 7aR) -2- (l, l-difluoropentyl) -2-hydroxy-6- pendant octahydrocyclopenta [b] pyran-5-yl] heptanoic acid (lubiprostone); (-)-7-{(2R, 4aR, 5R, 7aR) -2-[(3S) -l, l-difluoro-3-methylpentyl] -2-hydroxy-6-oxooctahydrocyclopenta [b] pyran-5-yl } Heptanoic acid (coprostol); (+)-isopropyl (Z) -7-[(lR, 2R, 3R, 5S) -3,5-dihydroxy-2- (3-oxodecane (Yl) cyclopentyl] hept-5-enoate (isopropyl unoprostone); (Z) -7-[(lR, 2R, 3R, 5S) -3,5-dihydroxy-2- ( 3-oxodecyl) cyclopentyl] hept-5-enoic acid; (-)-7-[(lR, 2R) -2- (4,4-difluoro-3-oxooctyl) -5-oxo-cyclopentyl] heptanoic acid; and (E) -7-[(lR, 2R) -2- (4,4-difluoro-3-oxo-octyl) -5-oxo Cyclopentyl] hept-2-enoic acid. The solid formulation of claim 26, wherein the drug is lubiprostone. The solid formulation according to any one of claims 25 to 27, wherein the drug is in a relative portion of drug to polymer ranging from 1 part drug per 0.2 parts polymer to up to 200 parts polymer and 400 parts polymer There is a range of substances, every 500 parts of polymer, every 1,000 parts of polymer, and about 1 part of medicine per 10,000 parts of polymer. A pharmaceutical composition comprising the solid dispersion according to any one of claims 25 to 28 and a pharmaceutically acceptable excipient, wherein the medicine is present in a pharmaceutically effective amount to treat a gastrointestinal disorder. The pharmaceutical composition as described in any one of the preceding pharmaceutical compositions, wherein the pharmaceutical composition is a solid dosage form, when USP type 2 dissolution device is used in 810 ml of neutral water and 90 ml of 1N HCl at 37 ° C and 200 rpm When measured, the solid dosage form releases at least 70% of the amount of drug contained in the dosage form within 30 minutes. The multilayer bead according to any one of claims 1 to 10, which has an outer layer comprising a polymer that is insoluble at a pH in the range of 5 to 8, and is in the range of 1 to 4 It is soluble at a pH in the range of; or insoluble at a pH in the range of 6 to 8 and soluble at a pH in the range of 1 to 5. The multi-layer bead according to any one of claims 1 to 10, wherein the layer is sprayed. The multilayer bead of claim 32, wherein the layer is sprayed and the solvent used for spraying is acetone. The multi-layer bead according to claim 32 or 33, wherein the spraying is performed at a temperature not exceeding 30 ° C. The multilayer bead according to any one of claims 32 to 34, wherein the coating is dried at a temperature not exceeding 45 ° C. A solid pharmaceutical formulation comprising the solid formulation of the drug of claim 25 in a polymer, wherein the solid formulation is in the form of particles, and optionally, one or more pharmaceutically acceptable excipients . As in the solid pharmaceutical formulation of claim 36, when measured at 37 ° C and 200 rpm in 810 ml of neutral water and 90 ml of 1N HCl using a USP Type 2 dissolution device, the solid pharmaceutical formulation is released for at least 30 minutes 70% of lubiprostone or its pharmaceutically acceptable salts, isomers, metabolites or prodrugs. The solid pharmaceutical formulation of claim 36, wherein the pharmaceutically acceptable excipient is one or more fillers, extenders, binding agents, humectants, disintegrants, absorption enhancers, wetting agents, adsorbents , Lubricants, plasticizers or buffers. The solid pharmaceutical formulation of claim 38, wherein the pharmaceutically acceptable excipients are starch, lactose, sucrose, glucose, mannitol, silicic acid, alginate, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, Acacia, glycerin, agar, calcium carbonate, croscarmellose sodium, complex silicate, sodium carbonate, paraffin, quaternary ammonium compound, cetyl alcohol, glycerol monostearate, magnesium stearate, Calcium stearate, sodium lauryl sulfate, kaolin, bentonite, talc, polyethylene glycol, or a mixture thereof. The solid pharmaceutical formulation of claim 39, wherein the pharmaceutically acceptable excipient is talc, polyethylene glycol, or a combination thereof. A method for treating chronic idiopathic constipation, opioid-induced constipation, and constipation associated with intestinal irritability, the method comprising the step of administering the solid pharmaceutical composition according to claim 36 to a patient in need of treatment . The method of claim 41, wherein the patient is a pediatric patient or an elderly patient. The pharmaceutical composition according to any one of claims 12 to 14, wherein the pharmaceutical composition is a solid oral dosage form. The solid oral dosage form of claim 43, wherein the solid oral dosage form contains 24 µg lubiprostone. As in the solid oral dosage form of claim 44, the solid oral dosage form releases at least 70% in 30 minutes at 37 ° C and 200 rpm in 810 ml of neutral water and 90 ml of 1N HCl using a USP Type 2 dissolution device The amount of medicine contained in the dosage form. The solid oral dosage form of claim 43, wherein the pharmaceutically acceptable excipient contained in the pharmaceutical formulation is one or more fillers, extenders, binding agents, moisturizers, disintegrants, absorption enhancers, Wetting agent, adsorbent, lubricant, plasticizer or buffer. The solid oral dosage form of claim 46, wherein the pharmaceutically acceptable excipients are starch, lactose, sucrose, glucose, mannitol, silicic acid, alginate, alginic acid, gelatin, polyvinylpyrrolidone, sucrose, arabin Gum, glycerin, agar, calcium carbonate, croscarmellose sodium, complex silicate, sodium carbonate, paraffin, quaternary ammonium compound, cetyl alcohol, glycerol monostearate, magnesium stearate, hard Calcium fatty acid, sodium lauryl sulfate, kaolin, bentonite, talc, polyethylene glycol, or a mixture thereof. The solid oral dosage form of claim 47, wherein the pharmaceutically acceptable excipient is talc, polyethylene glycol, or a combination thereof. A method for treating chronic idiopathic constipation, opioid-induced constipation, constipation associated with intestinal mania or functional constipation in children, the method comprising administering the solid oral dosage form according to any one of claims 43 to 48 Steps for patients in need. The method of claim 49, wherein the patient is a pediatric patient or an elderly patient. A multilayer bead comprising: a. A core particle comprising microcrystalline cellulose; b. A barrier layer coated on the surface of the core particle, the barrier layer comprising vinylpyrrolidone-vinyl acetate copolymer C. A polymer drug coating layer, which is coated on the surface of the barrier layer, the polymer drug coating layer comprises a therapeutically effective amount of lubiprostone or a pharmaceutically acceptable salt, isomer, Metabolites or prodrugs and vinylpyrrolidone-vinyl acetate copolymer; d. A sealing layer coated on the surface of the polymer coating layer, the sealing layer containing vinylpyrrolidone-vinyl acetate copolymer; And e. An outer layer coated on the surface of the sealing layer, the outer layer comprising a copolymer containing butyl methacrylate. The multilayer bead of claim 51, wherein the barrier layer, outer layer, or any combination thereof, comprises one or more pharmaceutically acceptable excipients. The multilayer bead of claim 52, wherein the one or more pharmaceutically acceptable excipients is talc, polyethylene glycol, or a combination thereof. The multilayer bead of claim 51, wherein one or more pharmaceutically acceptable excipients are included between any two layers of the multilayer bead. The multilayer bead of claim 54, wherein the one or more pharmaceutically acceptable excipients is talc. The multilayer bead of claim 51, wherein the lubiprostone is present in the polymer drug coating layer as a blend of the drug in the polymer. The multilayer bead of claim 56, wherein the amount of lubiprostone present in the multilayer bead is from about 0.01 µg to about 0.2 µg. The multilayer bead of claim 57 wherein the amount of lubiprostone present in the multilayer bead is from about 0.02 µg to about 0.1 µg. The multilayer bead of claim 58, wherein the amount of lubiprostone present in the multilayer bead is from about 0.04 µg to about 0.08 µg. The multi-layer bead of claim 56, wherein the lubiprostone is present in the polymer in an amount ranging from 1 part lubiprostone per 0.2 parts polymer to 1 part lubiprostone per 10,000 parts polymer In the medicine layer. The multilayer bead of claim 56, wherein the lubiprostone is present in the polymer in an amount ranging from 1 part lubiprostone per 0.2 parts polymer to 1 part lubiprostone per 1,000 parts polymer In the medicine layer. The multi-layer bead of claim 56, wherein the lubiprostone is present in the polymer in an amount ranging from 1 part lubiprostone per 0.2 parts polymer to 1 part lubiprostone per 500 parts polymer In the medicine layer. The multilayer bead of claim 56, wherein the lubiprostone is present in the polymer in an amount ranging from 1 part lubiprostone per 0.2 parts polymer to 1 part lubiprostone per 400 parts polymer In the medicine layer. The multi-layer bead of claim 56, wherein the lubiprostone is present in the polymer in an amount ranging from 1 part lubiprostone per 0.2 parts polymer to 1 part lubiprostone per 200 parts polymer In the medicine layer. The multi-layer bead of claim 56, wherein the lubiprostone is present in the polymer in an amount ranging from 1 part lubiprostone per 0.2 parts polymer to 1 part lubiprostone per 200 parts polymer In the medicine layer. A capsule comprising a plurality of multi-layer beads as in claim 51. The capsule of claim 66, wherein the amount of lubiprostone present in the multilayer bead is about 1 µg to about 75 µg. The capsule of claim 67, wherein the amount of lubiprostone present in the multilayer bead is about 24 µg. A method for treating chronic idiopathic constipation, opioid-induced constipation, or constipation associated with intestinal irritability, the method comprising the step of administering the capsule as in claim 66 to a patient in need thereof. The method of claim 69, wherein the patient is a pediatric patient or an elderly patient.